Investigators from McGill University have discovered a new link connecting immune cells and the development of gastric tumors in those with Peutz-Jeghers Syndrome (PJS), a hereditary cancer syndrome characterized by the development of gastrointestinal (GI) polyps.
Specifically, the team found that abnormal inflammation elicited by the immune system could lead to cancer progression in patients with PJS. With the newfound data, investigators deduced that targeting deregulated inflammation could be possible therapeutic approaches.
“Basically, our work changes the way we have been thinking about this disease, with our focus now on understanding how the immune system contributes to polyp development,” said Russell Jones,
BSc, Goodman Cancer Research Centre, Department of Physiology, McGill, in a recent statement
. “We hope that our discovery will lead to new treatments for PJS patients and others with gastrointestinal cancers. We’re pretty excited about it.”
Previous research has found that mutations in the tumor suppressor gene STK11—
which encodes liver kinase B1 (LKB1)—were found to cause benign polyps in the gut and a higher risk of several cancers in patients with PJS. In fact, patients with PJS above the age of 65 are estimated to have a 90% chance of developing cancer of the pancreas, stomach, ovaries, cervix, colon, or breast. “LKB1's role in this disease is thought to be related to its tumor suppressor function,” study authors write.
As such, investigators have long-focused their efforts on understanding the role of the STK11
gene in the epithelial cells of the gastrointestinal (GI) tract, where polyps—and tumors—typically form.
However, upon an accidental observance made by Julianna Blagih, PhD, that mice with disruption solely in the STK11
gene in T cells developed gastrointestinal tumors comparative to those found in individuals with PJS in the Jones Lab, Dr. Blagih and Dr. Jones redirected their attention from the STK11
gene to immune cells and their potential contribution to the development of PJS.
The team found that GI polyposis is promoted by heterozygous deletion of Stk11
in T cells in mice (LThet
mice). “Polyps from LThet
mice, and human PJS patients display hallmarks of chronic inflammation, marked by inflammatory immune-cell infiltration, signal transducer and activator of transcription 3 (STAT3) activation, and increased expression of inflammatory factors associated with cancer progression [interleukin 6 (IL-6), IL-11, and CXCL2],” the authors write. Simply, polyps from the LThet
mice and PJS patients contained telltale signs of inflammation.
Additionally, since reduced polyp growth in Stk11+/−
animals occurred when T cells, IL-6, or STAT3 signaling were targeted, LKB1-mediated inflammation was identified as a tissue-extrinsic regulator of intestinal polyposis in PJS, according to the authors; this suggests that targeting deregulated inflammation in PJS could be a potential therapeutic approach for the disease.
“This is a great example of how a random discovery in fundamental science in the lab can lead to new ideas about how diseases are caused, and potentially also to new treatments,” added Dr. Jones, corresponding author of the study and associate professor in the department of Physiology and the Goodman Cancer Research Centre at McGill. “When we investigated further, we confirmed that these were not simply random results and that the mice with T cells with these mutations developed inflammation in their gastrointestinal tract and polyps similar to those in PJS patients.”
Looking forward, the Jones Lab team plans to continue working with preclinical mouse models and collaborate with colleagues at the McGill University Health Centre (MUHC) to further study the role of inflammation in PJS.